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COMMON PART

Project Number18-73-00019

Project titleNew heterogeneously catalytic methods for producing oxo-derivatives of betulin

Project LeadKOLOBOVA EKATERINA

AffiliationNational Research Tomsk Polytechnic University,

Research area 03 - CHEMISTRY AND MATERIAL SCIENCES, 03-403 - Homogeneous catalysis and heterogeneous catalysis

Keywordsbetulin, oxo-derivatives of betulin, liquid-phase selective oxidation of betulin, silver and gold-containing catalysts, nanoparticles, active site nature , design and genesis of active surface

PROJECT CONTENT

Annotation
The use of natural compounds as objects of chemical transformations for the purpose of obtaining biologically active compounds has become one of the promising and actively developing trends in fine organic synthesis and pharmaceutical chemistry. Medicinal products obtained by chemical modification of natural compounds have a number of advantages in comparison with synthetic analogues: a broad spectrum of biological action, relatively low toxicity, a multifunctional mechanism of action and high availability of sources. Compounds that combine accessibility (the prevalence in nature and manufacturability of isolation methods, which allow obtaining virtually any amount of substance required) with valuable biological activity, is rich in the class of tryptenoids, among which betulin (lup-20 (29) -en-3, 28-diol, C30H50O2, CAS: 473-98-3) is the pentacyclic truperenoid of the lupan series. Betulin, and in particular its oxo derivatives (betulon, betulin and betulonic aldehydes, betulinic and betulonic acids, and their derivatives) have valuable biologically active properties and are of exceptional interest to the pharmaceutical, cosmetic and food industries. For example, betulinic acid and its derivatives exhibit high anticancer, anti-HIV, antiviral, anti-inflammatory, antiseptic, antimicrobial, antimalarial, anti-leishmaniasis, anthelmintic, fungicidal activity. Due to selective cytotoxicity against cancer cells and a satisfactory therapeutic index, betulinic acid is considered to be a promising chemotherapeutic agent against cancer. The 3-oxo-derivative of betulinic acid-betulonic acid-has a pronounced anti-inflammatory, antimelanic and antiviral effect. Antiviral and anti-leukemic activity of betulonic aldehyde is known. In the synthesis of biologically active compounds, a 3-oxo derivative of betulin, betulone, is also of special interest. The popularity of betulin derivatives, as precursors for the creation of new generation drugs, is steadily growing every year, as evidenced by numerous publications in the world's leading journals. Almost all leading universities in the world have research groups dealing with the chemistry of betulin and its derivatives, as well as the study of the biological activity of these compounds. However, despite a large number of works, almost all of them are devoted to medical and biochemical aspects, as well as chemical modification of oxo-derivatives of betulin. At the same time, issues related to the development of new methods for the preparation of these derivatives (betulon, betulin and betulonic aldehydes, betulin and betulonic acids) are practically unaffected. And the main method for the production of oxo derivatives of betulin is still its oxidation in a strongly acidic medium using the toxic reagent Jones, with some modification of this method (the use of various acids, solvents, etc.). However, this method has significant drawbacks. Thus, there is an urgent need to create new methods and approaches to the production of oxo-derivatives of betulin, which would replace the existing stoichiometric processes that lead to the formation of a large amount of toxic waste, but at the same time ensure the quantitative yield of the target product and its reduction in cost. Solving this problem in the long term will allow creating our own raw materials base in Russia to ensure the ever-growing demand for oxo derivatives of betulin, as precursors for obtaining new-generation drugs. And the most promising way to solve this problem, in our opinion, is the development of new heterogeneous catalytic methods for the production of oxo-derivatives of betulin, based on the use of environmentally friendly and cheap oxidants, molecular oxygen or air, and also allowing the process to be carried out under rather mild conditions, close to the requirements of "green chemistry" (the absence of alkaline and initiating additives in the reaction medium, moderate temperatures and pressures, low-toxic reagents). The foregoing determines the relevance of this project, which is a complex interdisciplinary study devoted to both the fundamental aspects of the design and genesis of the active surface of catalytic systems based on silver and gold nanoparticles (the nature of the active site, the mechanism of the modifying additives' promoting action, the influence of various factors on the formation of active sites, and .d.), and their practical application in the process of synthesis of oxo-derivatives of betulin. The novelty of this project is that: 1) For the first time, a new more efficient and environmentally safe heterogeneous catalytic method for the synthesis of oxo-derivatives of betulin (betulone, betulin and betulonic aldehydes, betulinic and betulonic acids) will be developed using catalytic systems based on gold and silver, and as an oxidizer-oxygen or air. Will the optimal conditions for carrying out the oxidation process (nature of catalyst, nature of solvent, reaction temperature, stirring speed, flow rate of the oxidizer, the ratio of substrate/catalyst, etc.), similar to the requirements of "green chemistry". 2) For the first time, a comprehensive comparative study of gold and silver catalysts will be conducted, including the study of the structural, electronic and catalytic properties of these systems in the process of betulin liquid-phase oxidation and the conditions for their effective operation close to the requirements of "green chemistry". It should also be noted that at the moment there are practically no studies devoted to the study of the reactivity of silver-containing systems in the processes of liquid-phase oxidation of both alcohols and other organic substances (we managed to find only about 20 works since 1969). However, the preliminary studies show the prospects of the use of silver-containing catalysts in this kind of processes and open up a new area of research. The conducted researches will allow to obtain information on the nature of active sites of silver- and gold-containing catalysts in the process of betulin liquid-phase oxidation, the laws of their formation and stabilization under the influence of a number of factors, such as the nature of support and the modifying additive, the conditions of synthesis, pretreatment, operation; to find approaches of purposeful influence on the state and reactivity of active sites; to develop methods of stabilization of active sites of silver and gold on the surface of supports and, as a result, to develop recommendations on directed synthesis of high-performance catalysts of selective liquid-phase oxidation of betulin. The project will be implemented jointly with the Center of Nanoscience and Nanotechnology of the National Autonomous University of Mexico (CNyN-UNAM), Ensenada, Mexico; Catalysis and Petrochemistry Institute, Madrid, Spain; University of Cadiz, Cadiz, Spain; Abo Academy, Turku, Finland, as well as a number of Russian scientific organizations: Tomsk State University, Tomsk; Institute of Petroleum Chemistry SB RAS, Tomsk; National Research Center "Kurchatov Institute", Moscow; Moscow State University. M.V. Lomonosov, Moscow.

Expected results
1. New stable and effective nanometallic catalyst systems based on silver and gold will be developed for the liquid phase selective oxidation of betulin; 2. Optimum conditions for carrying out the process of liquid phase oxidation of betulin (the nature of the solvent, the reaction temperature, the stirring rate, the oxidizer consumption, the substrate/catalyst ratio, the addition (or absence) of solid basic and dehydrating agents, etc.) will be determined for quantitative production a certain oxo-derivative betulin; 3. The dynamics of changes in the Ag(Au)/modifier/ support system (structural, electronic, and catalytic properties) will be studied in detail, depending on a number of factors - the method of preparation of the catalyst, the nature of the carrier and the modifying additive, the content of the active component, the conditions of preliminary treatments, etc. 4. Based on the obtained results, ideas on the nature of the active sites of nanoscale silver and gold catalysts during the liquid phase oxidation of betulin, the patterns of their formation and stabilization will be developed; approaches of targeted influence on the state and reactivity of active sites will be found; methods will be developed for stabilizing the active states of silver and gold on support surface; 5. Recommendations on directed synthesis and practical application of silver and gold-containing catalysts in the process of liquid phase oxidation of betulin will be developed. 6. Based on the obtained results, at least 2 articles will be published in journals indexed in the Scopus and/or Web of Science databases with IF > 1. Within the framework of the project, a number of fundamental (active surface organization, active site nature, the mechanism of the promoting action of modifying additives, etc.) and applied (a method for synthesizing catalysts will be developed, optimum conditions for the liquid phase oxidation of betulin will be determined; state and reactivity of active sites, etc.) tasks will be solved. The obtained results will make a significant contribution to the development of the theory and practice of the development of high-efficiency catalysts based on silver and gold for the process of selective liquid-phase oxidation of betulin, and in the future will allow the creation of an own raw material base in Russia for the production of oxo-derivatives of betulin, which in turn stimulates research on the creation of new generation drugs based on these derivatives. The results of the studies can be used in further scientific work concerning the production of oxo-derivatives of betulin and the study of their biological activity. The results can be used in lecture courses of universities of chemical and medical orientation, in research and industrial organizations specializing in the field of heterogeneous catalysis, nanotechnology and pharmaceutical chemistry, including at Tomsk Polytechnic University and partner universities of the project.

REPORTS